Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with clinical deficits ranging from relapsing-remitting to chronic-progressive patterns of expression. Although the etiology of MS is unknown, autoreactive CD4+ T cell responses mediate inflammatory damage against myelin and oligodendrocytes. (Bruck et al., J. Neurol. Sci. 206, 181-185 (2003)). CNS lesions have focal areas of myelin damage and are also associated with axonal pathology, neural distress, and astroglial scar formation (Compston et al., Lancet 359, 1221-1231 (2002)). Clinical presentation includes various neurological dysfunctions including blindness, paralysis, loss of sensation, as well as coordination and cognitive deficits.
Damage or injury to myelin has severe consequences on conduction velocity and the vulnerability of neurons to axonal destruction. There is a correlation between axon loss and progressive clinical disability and intact myelin is important in the maintenance of axonal integrity (Dubois-Dalcq et al., Neuron 48, 9-12 (2005)). Spontaneous remyelination occurs during the early phases of human MS, however, persistent CNS inflammation and the failure of myelin repair during later stages of the disease ultimately lead to permanent debilitation.
It is well accepted that adult oligodendrocyte progenitor cells are responsible for remyelination, and thus, the failure of remyelination is most likely associated with deficiencies in the generation of mature oligodendrocytes, their ability to myelinate, and/or neurodegeneration and axons that are not receptive to myelination.
Myelination relies on the coordination of multiple signals including those that precisely localize oligodendrocytes and their precursors (Tsai et al., Cell 110:373-383 (2002); Tsai et al., J. Neurosci. 26: 1913-22. (2006)), regulate appropriate cell numbers (Barres et al., Cell 70:31-46 (1992); Calver et al., Neuron 20:869-882 (1998)), and mediate interactions between oligodendrocytes and their target axons (Sherman and Brophy, Nat Rev Neurosci. 6:683-690 (2005)). Cell cycle exit is required for terminal differentiation of many cell types. By targeting components of cell cycle for neural cells involved in myelination, new strategies can be developed that enhance remyelination in myelin related disorders.
For example, by understanding what regulates the generation of oligodendrocytes (OLs), the myelin forming cells of the CNS can be regulated to promote differentiation or proliferation of progenitor cells. In other words, a “clock” that times precursor cells can be regulated to timing of OL differentiation and/or proliferation. While extrinsic cues that trigger such a clock with respect to oligodendrocyte progenitor cells (OPCs) may have been characterized, the components of the intracellular timer that intrinsically regulate when an OPC will differentiate remain largely uncharacterized.
There remains a need to develop effective methods for enhancing myelination. The present invention provides compositions and methods directed to promoting or regulating neural cell proliferation and differentiation thus promoting myelin repair. The findings disclosed herein will show a novel aspect of the mechanism by which OPCs keep time, which can be extended to similar clocks in many other precursor cell types.